Pentafluorobenzenesulfonamides and analogs

ABSTRACT

The invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly atherosclerosis and hypercholesterolernia, or as lead compounds for the development of such agents. The compositions include compounds of the general formula I:

This application is a continuation of U.S. Ser. No. 08/896,827, filedJul. 18, 1997, now U.S. Pat. No. 5,880,151, which is a continuation inpart of U.S. Ser. No. 08/605,431, filed Feb. 22, 1996, now abandoned thedisclosures of each are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The field of the invention is pentafluorobenzenesulfonamide derivativesand analogs and their use as pharmacologically active agents.

BACKGROUND

Atherosclerosis is a leading cause of death in the United States. Thedisease results from excess cholesterol accumulation in the arterialwalls which forms plaques that inhibit blood flow and promote clotformation, ultimately causing heart attacks, stroke and claudication.The principal source of these cholesterol deposits are low-densitylipoprotein (LDL) particles that are present in the blood. There is adirect correlation between LDL concentration and plaque formation in thearteries. LDL concentration is itself largely regulated by the supply ofactive LDL cell surface receptors which bind LDL particles andtranslocate them from the blood into the cell interior. Accordingly, theregulation of LDL receptor expression provides an important therapeutictarget.

Lipoprotein disorders have been previously called thehyperlipoproteinemias and defined as elevation of a lipoprotein levelabove normal. The hyperlipoproteinemias result in elevations ofcholesterol, triglycerides or both and are clinically important becauseof their contribution to atherosclerotic diseases and pancreatitis.

Lipoproteins are spherical macromolecular complexes of lipid andprotein. The lipid constituents of lipoproteins are esterified andunesterified (free) cholesterol. triglycerides, and phospholipids.Lipoproteins transport cholesterol and triglycerides from sites ofabsorption and synthesis to sites of utilization. Cholesteryl ester andtriglycerides are nonpolar and constitute the hydrophobic core oflipoproteins in varying proportions. The lipoprotein surface coatcontains the polar constituents--free cholesterol, phospholipids, andapolipoproteins--that permit these particles to be miscible in plasma.

Cholesterol is used for the synthesis of bile acids in the liver, themanufacture and repair of cell membranes, and the synthesis of steroidhormones. There are both exogenous and endogenous sources ofcholesterol. The average American consumes about 450 mg of cholesteroleach day and produces an additional 500 to 1,000 mg in the liver andother tissues. Another source is the 500 to 1,000 mg of biliarycholesterol that is secreted into the intestine daily; about 50 percentis reabsorbed (enterohepatic circulation). The rate-limiting enzyme inendogenous cholesterol synthesis is 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase. Triglycerides, which are nonpolar lipidsconsisting of a glycerol backbone and three fatty acids of varyinglength and degrees of saturation, are used for storage in adipose tissueand for energy.

Lipoproteins are classified into groups based upon size, density,electrophoretic mobility, and lipid and protein composition. Very lowdensity lipoproteins (VLDL) are large, triglyceride-rich lipoproteinsthat are synthesized and secreted by hepatocytes. VLDL interacts withlipoprotein lipase in capillary endothelium, and the core triglyceridesare hydrolyzed to provide fatty acids to adipose and muscle tissue.About half of the catabolized VLDL particles are taken up by hepatic LDLreceptors and the other half remain in plasma, becomingintermediate-density lipoprotein. IDL is enriched in cholesteryl esterrelative to triglyceride and is gradually converted by hepatictriglyceride lipase to the smaller, denser, cholesterol ester-rich LDL.As IDL is converted to LDL, apolipoprotein E becomes detached, and onlyone apolipoprotein remains, apo B-100.

LDL normally carries about 75 percent of the circulating cholesterol.Cellular LDL uptake is mediated by a glycoprotein receptor molecule thatbinds to apo B-100. Approximately 70 percent of LDL is cleared byreceptor uptake, and the remainder is removed by a scavenger cellpathway using nonreceptor mechanisms. The LDL receptors span thethickness of the cell's plasma membrane and are clustered in specializedregions where the cell membrane is indented to form craters calledcoated pits. These pits invaginate to form coated vesicles, where LDL isseparated from the receptor and delivered to a lysosome so thatdigestive enzymes can expose the cholesteryl ester and cleave the esterbond to form free cholesterol. The receptor is recycled to the cellsurface.

As free cholesterol liberated from LDL accumulates within cells, thereare three important metabolic consequences. First, there is a decreasein the synthesis of HMG-CoA reductase, the enzyme that controls the rateof de novo cholesterol synthesis by the cell. Second, there isactivation of the enzyme acyl cholesterol acyltransferase (ACAT), whichesterifies free cholesterol into cholesterol ester, the cell's storageform of cholesterol. Third, accumulation of cholesterol suppresses thecell's synthesis of new LDL receptors. This feedback mechanism reducesthe cell's uptake of LDL from the circulation.

Lipoproteins play a central role in atherogenesis. This association withthe most common cause of death in the developed world defines theprincipal clinical importance of the hyperlipoproteinemias. Individualswith an elevated cholesterol level are at higher risk foratherosclerosis. Multiple lines of evidence, including epidemiological,autopsy, animal studies and clinical trials, have established that LDLis atherogenic and that the higher the LDL level, the greater the riskof atherosclerosis and its clinical manifestations. A certain level ofLDL elevation appears to be a necessary factor in the development ofatherosclerosis, although the process is modified by myriad otherfactors (e.g., blood pressure, tobacco use, blood glucose level,antioxidant level, and clotting factors). Acute pancreatitis is anothermajor clinical manifestation of dyslipoproteinemia. It is associatedwith chylomicronemia and elevated VLDL levels. Most patients with acutepancreatitis have triglyceride levels above 2,000 mg/dL, but a 1983 NIHconsensus development conference recommended that prophylactic treatmentof hypertriglyceridemia should begin when fasting levels exceed 500mg/dL. The mechanism by which chylomicronemia and elevated VLDL causepancreatitis is unclear. Pancreatic lipase may act on triglyceride inpancreatic capillaries, resulting in the formation of toxic fatty acidsthat cause inflammation.

Abundant evidence indicates that treatment of hyperlipoproteinemia willdiminish or prevent atherosclerotic complications. In addition to a dietthat maintains a normal body weight and minimizes concentrations oflipids in plasma, therapeutic agents that lower plasma concentrations oflipoproteins, either by diminishing the production of lipoproteins or byenhancing the efficiency of their removal from plasma, are clinicallyimportant.

The most promising class of drugs currently available for the treatmentof hyperlipoproteinemia or hypercholesterolemia acts by inhibitingHMG-CoA reductase, the rate-limiting enzyme in endogenous cholesterolsynthesis. Drugs of this class competitively inhibit the activity of theenzyme. Eventually, this inhibition leads to a decrease in theendogenous synthesis of cholesterol and by normal homeostaticmechanisms, plasma cholesterol is taken up by LDL receptors to restorethe intracellular cholesterol balance.

Through both the release of precursors of LDL and receptor-mediated LDLuptake from the serum, liver cells play a critical role in maintainingserum cholesterol homeostasis. In both man and animal models, an inversecorrelation appears to exist between liver LDL receptors andLDL-associated serum cholesterol levels. In general, higher hepatocytereceptor numbers result in lower LDL-associated serum cholesterollevels. Cholesterol released into hepatocytes can be stored ascholesteryl esters, converted into bile acids and released into the bileduct, or enter into an oxycholesterol pool. It is this oxycholesterolpool that is believed to be involved in end product repression of boththe genes of the LDL receptor and enzymes involved in the cholesterolsynthetic pathway.

Transcription of the LDL receptor gene is known to be repressed whencells have an excess supply of cholesterol, probably in the form ofoxycholesterol. A DNA sequence in the LDL receptor promoter region,known as the sterol response element (SRE), appears to confer thissterol end product repression. This element has been extensivelyinvestigated (Brown, Goldstein and Russell, U.S. Pat. Nos. 4,745,060 and4,935,363). The SRE can be inserted into genes that normally do notrespond to cholesterol, conferring sterol end product repression of thechimeric gene. The exact mechanism of the repression is not understood.Brown and Goldstein have disclosed methods for employing the SRE in ascreen for drugs capable of stimulating cells to synthesize LDLreceptors (U.S. Pat. No. 4,935,363). It would be most desirable if thesynthesis of LDL receptors could be upregulated at the level of geneexpression. The upregulation of LDL receptor synthesis at this leveloffers the promise of resetting the level of serum cholesterol at alower, and clinically more desirable, level. Presently, however, thereare no cholesterol lowering drugs that are known to operate at the levelof gene expression. The present invention describes methods andcompounds that act to inhibit directly or indirectly the repression ofthe LDL receptor gene, resulting in induction of the LDL receptor on thesurface of liver cells, facilitating LDL uptake, bile acid synthesis andsecretion to remove cholesterol metabolites and hence the lowering ofLDL-associated serum cholesterol levels.

Accordingly, it is one object of the present invention to providecompounds which directly or indirectly upregulate LDL receptor synthesisat the level of gene expression and are useful in the treatment ofhypercholesterolemia or hyperlipoproteinemia.

A further object of the present invention is to provide therapeuticcompositions for treating said conditions.

A further object of the invention is to provide therapeutic compositionsfor treating pancreatitis.

Still further objects are to provide methods for upregulating LDLreceptor synthesis, for lowering serum LDL cholesterol levels, and forinhibiting atherosclerosis.

Other objects, features and advantages will become apparent to thoseskilled in the art from the following description and claims.

SUMMARY OF THE INVENTION

The invention provides methods and compositions relating to novelpentafluorophenylsulfonamide derivatives and analogs and their use aspharmacologically active agents. The compositions find particular use aspharmacological agents in the treatment of disease states, particularlyhypercholesterolemia and atherosclerosis, or as lead compounds for thedevelopment of such agents.

In one embodiment, the invention provides for the pharmaceutical use ofcompounds of the general formula I and for pharmaceutically acceptablecompositions of compounds of formula I: ##STR2## or a physiologicallyacceptable salt thereof, wherein: Y is --S(O)-- or --S(O)₂ --;

Z is --NR¹ R² or --OR³, where R¹ and R² are independently selected fromhydrogen,

substituted or unsubstituted (C1-C10)alkyl,

substituted or unsubstituted (C1-C10)alkoxy,

substituted or unsubstituted (C3-C6)alkenyl,

substituted or unsubstituted (C2-C6)heteroalkyl,

substituted or unsubstituted (C3-C6)heteroalkenyl,

substituted or unsubstituted (C3-C6)alkynyl,

substituted or unsubstituted (C3-C8)cycloalkyl,

substituted or unsubstituted (C5-C7)cycloalkenyl,

substituted or unsubstituted (C5-C7)cycloalkadienyl,

substituted or unsubstituted aryl,

substituted or unsubstituted aryloxy,

substituted or unsubstituted aryl-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,

substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C1-C4)alkyl,

substituted or unsubstituted aryl-(C1-C4)alkoxy,

substituted or unsubstituted aryl-(C1-C4)heteroalkyl,

substituted or unsubstituted aryl-(C3-C6)alkenyl,

substituted or unsubstituted aryloxy-(C1-C4)alkyl,

substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,

substituted or unsubstituted heteroaryl,

substituted or unsubstituted heteroaryloxy,

substituted or unsubstituted heteroaryl-(C1-C4)alkyl,

substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,

substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,

substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and

substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,

wherein R¹ and R² may be connected by a linking group E to give asubstituent of the formula ##STR3## wherein E represents a bond, (C1-C4)alkylene, or (C1-C4) heteroalkylene, and the ring formed by R¹, E, R²and the nitrogen contains no more than 8 atoms, or preferably the R¹ andR² may be covalently joined in a moiety that forms a 5- or 6-memberedheterocyclic ring with the nitrogen atom of NR¹ R² ;

and where R³ is a substituted or unsubstituted aryl or heteroaryl group.

Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and cycloalkadienylradicals are selected independently from

--H

--OH

--O--(C1-C10)alkyl

═O

--NH₂

--NH--(C1-C10)alkyl

--N[(C1-C10)alkyl]₂

--SH

--S--(C1-C10)alkyl

-halo

--Si[(C1-C10)alkyl]₃

in a number ranging from zero to (2N+1), where N is the total number ofcarbon at ms in such radical.

Substituents for the aryl and heteroaryl groups are selectedindependently from

-halo

--OH

--O--R'

--O--C(O)--R'

--NH₂

--NHR'

--NR'R"

--SH

--SR'

--R'

--CN

--NO₂

--CO₂ H

--CO₂ --R'

--CONH₂

--CONH--R'

--CONR'R"

--O--C(O)--NH--R'

--O--C(O)--NR'R"

--NH--C(O)--R'

--NR"--C(O)--R'

--NH--C(O)--OR'

--NR"--C(O)--R'

--NH--C(NH₂)═NH

--NR'--C(NH₂)═NH

--NH--C(NH₂)═NR'

--S(O)--R'

--S(O)₂ --R'

--S(O)₂ --NH--R'

--S(O)₂ --NR'R"

--N₃

--CH(Ph)₂

substituted or unsubstituted aryloxy

substituted or unsubstituted arylamino

substituted or unsubstituted heteroarylamino

substituted or unsubstituted heteroaryloxy

substituted or unsubstituted aryl-(C1-C4)alkoxy ,

substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,

perfluoro(C1-C4)alkoxy, and

perfluoro(C1-C4)alkyl,

in a number ranging from zero to the total number of open valences onthe aromatic ring system;

and where R' and R" are independently selected from:

substituted or unsubstituted (C1-C10)alkyl,

substituted or unsubstituted (C1-C10)heteroalkyl,

substituted or unsubstituted (C2-C6)alkenyl,

substituted or unsubstituted (C2-C6)heteroalkenyl,

substituted or unsubstituted (C2-C6)alkynyl,

substituted or unsubstituted (C3-C8)cycloalkyl,

substituted or unsubstituted (C3-C8)heterocycloalkyl,

substituted or unsubstituted (C5-C6)cycloalkenyl,

substituted or unsubstituted (C5-C6)cycloalkadienyl,

substituted or unsubstituted aryl,

substituted or unsubstituted aryl-(C1-C4)alkyl,

substituted or unsubstituted aryl-(C1-C4)heteroalkyl,

substituted or unsubstituted aryl-(C2-C6)alkenyl,

substituted or unsubstituted aryloxy-(C1-C4)alkyl,

substituted or unsubstituted aryloxy-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl,

substituted or unsubstituted heteroaryl-(C1-C4)alkyl,

substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl-(C2-C6)alkenyl,

substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and

substituted or unsubstituted heteroaryloxy-(C1-C4)heteroalkyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringay optionally be replaced with a substituent of the formula--T--C(O)--(CH₂)_(n) --U--, wherein T and U are independently selectedfrom N, O, and C, and n=0-2. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula --A--(CH2)p--B--, wherein A and B areindependently selected from C, O, N, S, SO, SO₂, and SO₂ NR', and p=1-3.One of the single bonds of the new ring so formed ma optionally bereplaced with a double bond. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula --(CH₂)_(q) --X--(CH₂)_(r) --, where qand r are independently 1-3, and X is selected from O, N, S, SO, SO₂ andSO₂ NR'. The substituent R' in SO₂ NR' is selected from hydrogen or(C1-C6)alkyl.

In another embodiment, the invention provides novel methods for the useof pharmaceutical compositions containing compounds of the foregoingdescription of the general formula I. The invention provides novelmethods for treating pathology such as hypercholesterolemia,atherosclerosis, pancreatitis, and hyperlipoproteinemia, includingadministering to a patient an effective formulation of one or more ofthe subject compositions.

In another embodiment, the invention provides chemically-stable,pharmacologically active compounds of general formula I: ##STR4## or apharmaceutically acceptable salt thereof, wherein: Y is --S(O)-- or--S(O₂)--; and

Z is NR¹ R², wherein R² is an optionally substituted aryl or heteroarylgroup, and R¹ is selected from:

hydrogen,

substituted or unsubstituted (C1-C10)alkyl,

substituted or unsubstituted (C1-C10)alkoxy,

substituted or unsubstituted (C3-C6)alkenyl,

substituted or unsubstituted (C2-C6)heteroalkyl,

substituted or unsubstituted (C3-C6)heteroalkenyl,

substituted or unsubstituted (C3-C6)alkynyl,

substituted or unsubstituted (C3-C8)cycloalkyl,

substituted or unsubstituted (C5-C7)cycloalkenyl,

substituted or unsubstituted (C5-C7)cycloalkadienyl,

substituted or unsubstituted aryl,

substituted or unsubstituted aryloxy,

substituted or unsubstituted aryl-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,

substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C1-C4)alkyl,

substituted or unsubstituted aryl-(C1-C4)alkoxy,

substituted or unsubstituted aryl-(C1-C4)heteroalkyl,

substituted or unsubstituted aryl-(C3-C6)alkenyl,

substituted or unsubstituted aryloxy-(C1-C4)alkyl,

substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,

substituted or unsubstituted heteroaryl,

substituted or unsubstituted heteroaryloxy,

substituted or unsubstituted heteroaryl-(C1-C4)alkyl,

substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,

substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,

substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and

substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,

wherein R¹ and R² may be connected by a linking group E to give asubstituent of the formula ##STR5## wherein E represents a bond, (C1-C4)alkylene, or (C1-C4) heteroalkylene, and the ring formed by R¹, E, R²and the nitrogen contains no more than 8 atoms, or preferably the R¹ mdR² may be covalently joined in a moiety that forms a 5- or 6-memberedheterocyclic ring with the nitrogen atom of NR¹ R² ; provided that:

in the case that Y is --S(O₂)--, and R¹ is hydrogen or methyl, then R²is substituted phenyl or heteroaryl group;

in the case that Y is --S(O₂)-- and R² is a ring system chosen from1-naphthyl, 5-quinolyl, or 4-pyridyl, then either R¹ is not hydrogen orR² is substituted by at least one substituent that is not hydrogen;

in the case that Y is --S(O₂)--, R² is phenyl, and R¹ is a propyleneunit attaching the nitrogen of --NR¹ R² -- to the 2-position of thephenyl ring in relation to the sulfonamido group to form a1,2,3,4-tetrahydroquinoline system, one or more of the remainingvalences on the bicyclic system so formed is substituted with at leastone substituent that is not hydrogen;

in the case that Y is --S(O₂)-- and R² is phenyl substituted with3-(1-hydroxyethyl), 3-dimethylamino, 4-dimethylamino, 4-phenyl,3-hydroxy, 3-hydroxy-4-diethylaminomethyl, 3,4-methylenedioxy,3,4-ethylenedioxy, 2-(1-pyrrolyl), or 2-methoxy-4-(1-morpholino), theneither R¹ is not hydrogen or when R¹ is hydrogen, one or more of theremaining valences on the phenyl ring of R² is substituted with asubstituent that is not hydrogen;

in the case that Y is --S(O₂)-- and R² is 2-methylbenzothiazol-5-yl,6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl,5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl,3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl,2-trifluoromethyl-1,3,4-thiadiazol-5-yl, 5,6,7,8-tetrahydro-2-naphthyl,4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl,7-chloro-5-methyl-1,8-naphthyridin-2-yl,5,7-dimethyl-1,8-naphthyridin-2-yl, or 3-cyanopyrazol-4-yl, R¹ is agroup other than hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl" by itself or as part of another substituent means,unless otherwise stated, a straight or branched chain hydrocarbonradical, including di- and multi-radicals, having the number of carbonatoms designated (i.e. C1-C10 means one to ten carbons) and includesstraight or branched chain groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomersof n-pentyl, n-hexyl, 2-methylpentyl, 1,5-dimethylhexyl,1-methyl-4-isopropylhexyl and the like. The term "alkylene" by itself oras part of another substituent means a divalent radical derived from analkane, as exemplified by --CH₂ CH₂ CH₂ CH₂ --. A "lower alkyl" is ashorter chain alkyl, generally having six or fewer carbon atoms.

The term "heteroalkyl" by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainradical consisting of the stated number of carbon atoms and one or twoheteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) maybe placed at any position of the heteroalkyl group, including betweenthe rest of the heteroalkyl group and the fragment to which it isattached, as well as attached to the most distal carbon atom in theheteroalkyl group. Examples include --O--CH₂ --CH₂ --CH₃, --CH₂ --CH₂--O--CH₃, --CH₂ --CH₂ --CH₂ --OH, --CH₂ --CH₂ --NH--CH₃, --CH₂ --CH₂--N(CH₃)--CH₃, --CH₂ --S--CH₂ --CH₃, --CH₂ CH₂ --S(O)--CH₃, --O--CH₂--CH₂ --CH₂ --NH--CH₃, and --CH₂ --CH₂ --S(O)₂ --CH₃. Up to twoheteroatoms may be consecutive, such as, for example, --CH₂ --NH--OCH₃.The term "heteroalkylene" by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by--CH₂ --CH₂ --S--CH₂ --CH₂ -- and --CH₂ --S--CH₂ --CH₂ --NH--.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of "alkyl" and "heteroalkyl", respectively. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, cyclopentyl, and the like.Examples of heterocycloalkyl include 1-piperidinyl, 2-piperidinyl,3-piperidinyl 4-morpholinyl. 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The term "alkenyl" employed alone or in combination with other terms,means, unless otherwise stated, a stable straight chain or branchedmonounsaturated or diunsaturated hydrocarbon group having the statednumber of carbon atoms. Examples include vinyl, propenyl (allyl),crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, andthe higher homologs and isomers. A divalent radical derived from analkene is exemplified by --CH═CH--CH₂ --.

The term "heteroalkenyl" by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainmonounsaturated or diunsaturated hydrocarbon radical consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quarternized. Up to two heteroatoms may be placedconsecutively. Examples include --CH═CH--O--CH₃, --CH═CH--CH₂ --OH,--CH₂ --CH═N--OCH₃, --CH═CH--N(CH₃)--CH₃, and --CH₂ --CH═CH--CH₂ --SH.

The term "alkynyl" employed alone or in combination with other terms,means, unless otherwise stated, a stable straight chain or branchedhydrocarbon group having the stated number of carbon atoms, andcontaining one or two carbon-carbon triple bonds, such as ethynyl, 1-and 3-propynyl, 4-but-1-ynyl, and the higher homologs and isomers.

The term "alkoxy" employed alone or in combination with other termsmeans, unless otherwise stated, an alkyl group, as defined above,connected to the rest of the molecule via an oxygen atom, such as, forexample, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologsand isomers.

The terms "halo" or "halogen" by themselves or as part of anothersubstituent mean. unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

The term "aryl" employed alone or in combination with other terms,means, unless otherwise stated, a phenyl, 1-naphthyl, or 2-naphthylgroup. The maximal number of substituents allowed on each one of thesering systems is five, seven, and seven, respectively. Substituents areselected from the group of acceptable substituents listed above.

The term "heteroaryl" by itself or as part of another substituent means,less otherwise stated, an unsubstituted or substituted, stable, mono- orbicyclic heterocyclic aromatic ring system which consists of carbonatoms and from one to four heteroatoms selected from the groupconsisting of N, O, and S, and wherein the nitrogen and sulfurheteroatom may optionally be oxidized, and the nitrogen atom mayoptionally be quaternized. The heterocyclic system may be attached,unless otherwise stated at any heteroatom or carbon atom which affords astable structure. The heterocyclic system may be substituted orunsubstituted with on to four substituents independently selected fromthe list of acceptable aromatic substituents listed above. Examples ofsuch heterocycles include 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2 thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl.

Pharmaceutically acceptable salts of the compounds of Formula I includesalts of these compounds with relatively nontoxic acids or bases,depending on the particular substituents found on specific compounds ofFormula I. When compounds of Formula I contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of compound I with a sufficient amount of the desired base,either neat or in a suitable inert solvent. Examples of pharmaceuticallyacceptable base addition salts include sodium, potassium, calcium,ammonium, organic amino, or magnesium salt, or a similar salt. Whencompounds of Formula I contain relatively basic functionalities, acidaddition salts can be obtained by contacting the neutral form ofcompound I with a sufficient amount of the desired acid, either eat orin a suitable inert solvent. Examples of pharmaceutically acceptableacid addition salts include those derived from inorganic acids likehydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like gluconic or galactunoric acids and the like(see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journalof Pharmaceutical Science, Vol. 66, pages 1-19 (1977)). Certain specificcompounds of Formula I contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

The free base form may be regenerated by contacting the salt with a baseor acid and isolating the parent compound in the conventional manner.The parent form of the compound differs from the various salt forms incertain physical properties, such as solubility in polar solvents, butotherwise the salts are equivalent to the parent form of the compoundfor the purposes of the present invention.

Certain compounds of the present invention can exist in unsolvated formswell as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers); the racemates, diastereomers, and individualisomers are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium (³H) or carbon-14 (¹⁴ C). All isotopic variations of the compounds of thepresent invention, whether radioactive or not, are intended to beencompassed within the scope of the preset invention.

In various preferred embodiments of the pharmaceutical compositions ofcompounds of formula I, Y is S(O₂) and Z is NR¹ R², wherein R¹ ishydrogen or methyl, and R² is a substituted phenyl, preferably mono-,di-, or trisubstituted as follows. In one group of preferred compounds,Y is S(O₂) and Z is NR¹ R², wherein R¹ is hydrogen or methyl, and R² isa phenyl group, preferably substituted in the para position by one ofthe following groups: hydroxy, amino, (C1-C10)alkoxy, (C1-C10)alkyl,(C1-C10)alkylamino, and [di(C1-C10)alkyl]amino, with up to fouradditional substituents independently chosen from hydrogen, halogen,(C1-C10)alkoxy, (C1-C10)alkyl, and [di(C1-C10)alkyl]amino. Alsopreferred are compounds of formula I where there is no linking group Ebetween R¹ and R².

Illustrative examples of pharmaceutical compositions and compounds ofthe subject pharmaceutical methods include:

3-Fluoro-4-methoxy- 1-pentafluorophenylsulfinamidobenzene;

4-Dimethylamino-1-pentafluorophenylsulfinamidobenzene;

4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;

4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;

2-Pentafluorophenylsulfonamidothiophene;

3-Pentafluorophenylsulfonamidothiophene;

3-Pentafluorophenylsulfonamidopyridine;

4-Pentafluorophenylsulfonamidopyridine;

4-(N,N,-Dimethylamino)-1-(N-ethylpentafluorophenylsulfonamido)-benzene;

4-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;

3-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;

2-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;

4-Isopropoxy-1-pentafluorophenylsulfonarnidobenzene;

3-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;

2-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;

2-Methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;

4-Cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;

3-Fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;

3-Hydroxy-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;

1-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;

1-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;

1-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonarnidobenzene;

1,3-Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;

1-Pentafluorophenylsulfonylindole;

1-Pentafluorophenylsulfonyl(2,3-dihydro)indole;

1-Pentafluorophenylsulfonyl(1,2-dihydro)quinoline;

1-Pentafluorophenylsulfonyl(1,2,3,4-tetrahydro)quinoline;

3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene;

4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;

2-Chloro-5-pentafluorophenylsulfonamidopyridine;

2-Hydroxy-1-methoxy-4-[N-5-hydroxypent-1-yl)pentafluorophenyl-sulfonamido]benzene;

4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;

1-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;

2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;

1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;

3-Chloro-1-pentafluorophenylsulfonamidobenzene;

4-Chloro-1-pentafluorophenylsulfonamidobenzene;

3-Nitro-1-pentafluorophenylsulfonamidobenzene;

4-Methoxy-1-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene;

4-Methoxy-1-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene;

1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene;

4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene;

1-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene;

1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene

1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene;

1-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;

4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;

3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;

4-Butoxy-1-pentafluorophenylsulfonamidobenzene;

1-Pentafluorophenylsulfonamido-4-phenoxybenzene;

6-Pentafluorophenylsulfonamidoquinoline;

2,3-Dihydro-5-pentafluorophenylsulfonamidoindole;

5-Pentafluorophenylsulfonamidobenzo[a]thiophene;

5-Pentafluorophenylsulfonamidobenzo[a]furan;

3-Hydroxy-4-(1-propenyl)-1-pentafluorophenylsulfonamidobenzene;

4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene;

4-Methylmercapto-1-pentafluorophenylsulfonamidobenzene;

2-Methoxy-1-pentafluorophenylsulfonamidobenzene;

4-Allyloxy-1-pentafluorophenylsulfonamidobenzene;

1-Pentafluorophenylsulfonamido-4-propoxybenzene;

4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;

1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene;

1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;

4-(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene;

4-Amino-1-pentafluorophenylsulfonamidobenzene;

Pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamidoindazole;

4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonamido)-benzene;

1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;

3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene;

3-Ethoxy-1-pentafluorophenylsulfonamidobenzene;

7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;

3-Phenoxy-1-pentafluorophenylsulfonamidobenzene;

4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;

2-Hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;

1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;

3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;

3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene;

2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene;

4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonarnidobenzene,hydrochloride;

2-Methoxy-5-pentafluorophenylsulfonamidopyridine; and

2-Anilino-3-pentafluorophenylsulfonamidopyridine.

Examples of the most preferred pharmaceutical compositions and compoundsof the subject pharmaceutical methods include:

4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;

3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;

1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassiumsalt;

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassiumsalt;

4-Methoxy-1-pentafluorophenylsulfonamidobenzene;

3-Hydroxy-1-pentafluorophenylsulfonamidobenzene;

4-Hydroxy-1-pentafluorophenylsulfonamidobenzene;

1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamidoindole;

4-Ethoxy-1-pentafluorophenylsulfonamidobenzene;

3-Methoxy-1-pentafluorophenylsulfonamidobenzene;

2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;

2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;

1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;

4-Chloro-1-pentafluorophenylsulfonamidobenzene; and

3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.

The invention provides for certain novel compounds of general Formula Ithat possess one or more valuable biological activities such as apharmacologic, toxicologic, metabolic, etc. Exemplary compounds of thisembodiment of the invention include:

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

4-Dimethylamino-1-pentafluorophenylsulfonamidobenzene;

4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;

4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;

2-Pentafluorophenylsulfonamidothiophene;

3-Pentafluorophenylsulfonamidothiophene;

3-Pentafluorophenylsulfonamidopyridine;

4-Pentafluorophenylsulfonamidopyridine;

4-(N,N,-Dimethylamino)-1-(N-ethylpentafluorophenylsulfonamido)benzene;

4-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;

3-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;

2-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;

4-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;

3-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;

2-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;

2-Methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;

1-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;

1-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;

1-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene;

1,3-Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;

1-Pentafluorophenylsulfonylindole;

1-Pentafluorophenylsulfonyl(2,3-dihydro)indole;

1-Pentafluorophenylsulfonyl(1,2-dihydro)quinoline;

1-Pentafluorophenylsulfonyl(1,2,3,4-tetrahydro)quinoline;

3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene;

4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;

2-Chloro-5-pentafluorophenylsulfonamidopyridine;

2-Hydroxy-1-methoxy-4-[N-5-hydroxypent-1-yl)pentafluorophenyl-sulfonamido]benzene;

4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;

1-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;

2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;

1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;

3-Chloro-1-pentafluorophenylsulfonamidobenzene;

4-Chloro-1-pentafluorophenylsulfonamidobenzene;

3-Nitro-1-pentafluorophenylsulfonamidobenzene;

4-Methoxy-1-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene;

4-Methoxy-1-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene;

1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene;

4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene;

1-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene;

1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;

1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene;

1-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;

4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;

3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;

4-Butoxy-1-pentafluorophenylsulfonamidobenzene;

1-Pentafluorophenylsulfonamido-4-phenoxybenzene;

4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene;

4-Methylmercapto-1-pentafluorophenylsulfonarnidobenzene;

2-Methoxy-1-pentafluorophenylsulfonamidobenzene;

4-Allyloxy-1-pentafluorophenylsulfonamidobenzene;

1-Pentafluorophenylsulfonamido-4-propoxybenzene;

4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;

1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene;

1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;

4-(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene;

4-Amino-1-pentafluorophenylsulfonamidobenzene;

Pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamidoindazole;

4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonamido)-benzene;

1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;

3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene;

3-Ethoxy-1-pentafluorophenylsulfonamidobenzene;

7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;

3-Phenoxy-1-pentafluorophenylsulfonamidobenzene;

4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;

2-Hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;

1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;

4-Cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;

3-Fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;

6-Pentafluorophenylsulfonamidoquinoline;

2,3-Dihydro-5-pentafluorophenylsulfonamidoindole;

5-Pentafluorophenylsulfonamidobenzo[a]thiophene;

5-Pentafluorophenylsulfonamidobenzo[a]furan;

3-Hydroxy-4-(1-propenyl)-1-pentafluorophenylsulfonamidobenzene;

3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;

3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene;

2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene;

4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene,hydrochloride and,

2-Analino-3-pentafluorophenylsulfonamidopyridine.

Preferred compounds of this embodiment of the invention have specificpharmacological properties. Examples of the most preferred compounds ofthis embodiment of the invention include:

4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonarnidobenzene;

3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;

1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassiumsalt;

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassiumsalt;

4-Methoxy-1-pentafluorophenylsulfonamidobenzene;

3-Hydroxy-1-pentafluorophenylsulfonamidobenzene;

4-Hydroxy-1-pentafluorophenylsulfonamidobenzene;

1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene;

5-Pentafluorophenylsulfonamidoindole;

4-Ethoxy-1-pentafluorophenylsulfonamidobenzene;

3-Methoxy-1-pentafluorophenylsulfonamidobenzene;

2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;

2-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;

2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;

1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;

4-Chloro-1-pentafluorophenylsulfonamidobenzene; and

3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.

SYNTHESIS

Scheme I Syntheses of pentafluorophenylsulfonamides, sulfonic esters,sulfinamides, and sulfinic esters ##STR6## Scheme II Alternativesynthesis of N,N-disubstituted pentafluorophenylsulfonamides. ##STR7##Scheme III Syntheses of Phenols ##STR8## The invention provides methodsof making the subject compounds and compositions. In one generalembodiment, the methods involve combining pentafluorophenylsulfonylchloride with an amine having the general formula R¹ R² NH underconditions whereby the pentafluorophenylsulfonyl chloride and aminereact to form the desired compound, and isolating the compound.

Compounds with the generic structure 1 or 3 (Scheme I) may be preparedby reacting the appropriate starting amine in a solvent such astetrahydrofuran (THF), dimethylformamide (DMF), ether, toluene orbenzene in the presence of a base such as pyridine,p-dimethylaminopyridine, triethylamine, sodium carbonate or potassiumcarbonate and pentafluorophenylsulfonyl chloride orpentafluorophenylsulfinyl chloride, respectively. Pyridine itself mayalso be used as the solvent. Preferred solvents are pyridine and DMF andpreferred bases are pyridine, triethylamine, and potassium carbonate.This reaction can be carried out at a temperature range of 0° C. to 100°C., conveniently at ambient temperature.

Compounds of the generic structure 1 can also be obtained by treatingthe starting sulfonamide (Scheme II) with a base such as LDA, NaH,dimsyl salt, alkyl lithium, potassium carbonate, under an inertatmosphere such as argon or nitrogen, in a solvent such as benzene,toluene, DMF or THF with an alkylating group containing a leaving groupsuch a Cl, Br, I, MsO--, TsO--, TFAO--, represented by E in Scheme II. Apreferred solvent for this reaction is THF and the preferred base islithium bis(trimethylsilyl)amide. This reaction can be carried out at atemperature range of 0° C. to 100° C., conveniently at ambienttemperature.

Sulfonic esters (2) and sulfinic esters (4) may be prepared by reactingthe appropriate starting phenol in a solvent such as THF, DMF, tolueneor benzene in the presence of a base such as pyridine, triethylamine,sodium carbonate, potassium carbonate or 4-dimethylaminopyridine withpentafluorophenylsulfonyl chloride or pentafluorophenylsulfinylchloride, respectively. Pyridine itself may also be used as the solvent.Preferred solvents are pyridine and DMF and preferred bases are sodiumcarbonate and potassium carbonate. This reaction can be carried out at atemperature range of 0° C. to 100° C., conveniently at ambienttemperature.

Compounds of the general structure 5, in which Ar is an aromatic groupand x is from one to three, can be obtained from the correspondingmethyl ethers (Scheme III) by reaction with boron tribromide in asolvent of low polarity such as hexanes or CH₂ Cl₂ under an inertatmosphere at a temperature ranging from -45° to 30° C. In a preferredembodiment, the reaction is carried out in CH₂ Cl₂ at about 30° C.

Occasionally, the substrates for the transformations shown in SchemesI-III may contain functional groups (for example, amino, hydroxy orcarboxy) which are not immediately compatible with the conditions of thegiven reaction. In such cases, these groups may be protected with asuitable protective group, and this protective group removed subsequentto the transformation to give the original functionality using well knowprocedures such as those illustrated in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, Second Edition, John Wiley &Sons, Inc., 1991.

The compounds used as initial starting materials in this invention maybe purchased from commercial sources or alternatively are readilysynthesized by standard procedures which are well know to those ofordinary skill in the art.

Some of the compounds of formula I may exist as stereoisomers, and theinvention includes all active stereoisomeric forms of these compounds.In the case of optically active isomers, such compounds may be obtainedfrom corresponding optically active recursors using the proceduresdescribed above or by resolving racemic mixtures. The resolution may becarried out using various techniques such as chromatography, repeatedrecrystallization of derived asymmetric salts, or derivatization, whichtechniques are well known to hose of ordinary skill in the art.

The compounds of formula I which are acidic or basic in nature can formwide variety of salts with various inorganic and organic bases or acids,respectively. These salts must be pharmacologically acceptable foradministration to mammals. Salts of the acidic compounds of thisinvention are readily prepared by treating the acid compound with anappropriate molar quantity of the chosen inorganic or organic base in anaqueous or suitable organic solvent and then evaporating the solvent toobtain the salt. Acid addition salts of the basic compounds of thisinvention can be obtained similarly by treatment with the desiredinorganic or organic acid and subsequent solvent evaporation andisolation.

The compounds of the invention may be labeled in a variety of ways. Forexample, the compounds may be provided as radioactive isotopes; forexample, tritium and the ¹⁴ C-isotopes. Similarly, the compounds may beadvantageously joined, covalently or noncovalently, to a wide variety ofjoined compounds which may provide pro-drugs or function as carriers,labels, adjuvents, coactivators, stabilizers, etc. Hence, compoundshaving the requisite structural limitations encompass such compoundsjoined directly or indirectly (e.g. through a linker molecule), to suchjoined compounds.

ANALYSIS

The subject compositions were demonstrated to have pharmacologicalactivity in in vitro and in vivo assays, e.g. are capable ofspecifically modulating a cellular physiology to reduce an associatedpathology or provide or enhance a prophylaxis. Preferred compounds arecapable of specifically regulating LDL receptor gene expression.Compounds may be evaluated in vitro for their ability to increase LDLreceptor expression using western-blot analysis, for example, asdescribed in Tam et al. (1991) J. Biol. Chem. 266, 16764. Establishedanimal models to evaluate hypocholesterolemic effects of compounds areknown in the art. For example, compounds disclosed herein are shown tolower cholesterol levels in hamsters fed a high-cholesterol diet, usinga protocol similar to that described in Spady et al. (1988) J. Clin.Invest. 81, 300; Evans et al. (1994) J. Lipid Res. 35, 1634; Lin et al(1995) J. Med. Chem. 38, 277.

FORMULATION AND ADMINISTRATION

The invention provides methods of using the subject compounds andcompositions to treat disease or provide medicinal prophylaxis, toupregulate LDL receptor gene Expression in a cell, to reduce bloodcholesterol concentration in a host, etc. These methods generallyinvolve contacting the cell with or administering to the host aneffective amount of the subject compounds or pharmaceutically acceptablecompositions.

The compositions and compounds of the invention and the pharmaceuticallyacceptable salts thereof can be administered in any effective way suchas via oral, parenteral or topical routes. Generally, the compounds areadministered in dosages ranging from about 2 mg up to about 2,000 mg perday, although variations will necessarily occur depending on the diseasetarget, the patient, and the route of administration. Preferred dosagesare administered orally in the range of about 0.05 mg/kg to about 20mg/kg, more preferably in the range of about 0.05 mg/kg to about 2mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mgper kg of body weight per day.

In one embodiment, the invention provides the subject compounds combinedwith a pharmaceutically acceptable excipient such as sterile saline orother medium, water, gelatin, an oil, etc. to form pharmaceuticallyacceptable compositions. The compositions and/or compounds may beadministered alone or in combination with any convenient carrier,diluent, etc. and such administration may be provided in single ormultiple dosages. Useful carriers include solid, semi-solid or liquidmedia including water and non-toxic organic solvents.

In another embodiment, the invention provides the subject compounds inthe form of a pro-drug, which can be metabolically converted to thesubject compound by the recipient host. A wide variety of pro-drugformulations are known in the art.

The compositions may be provided in any convenient form includingtablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, suppositories, etc. As such the compositions, inpharmaceutically acceptable dosage units or in bulk, may be incorporatedinto a wide variety of containers. For example, dosage units may beincluded in a variety of containers including capsules, pills, etc.

The compositions may be advantageously combined and/or used incombination with other hypocholesterolemic and/or hypolipemictherapeutic or prophylactic agents, different from the subjectcompounds. In many instances, administration in conjunction with thesubject compositions enhances the efficacy of such agents. Exemplaryhypocholesterolemic and/or hypolipemic agents include: bile acidsequestrants such as quaternary amines (e.g. cholestyramine andcolestipol); nicotinic acid and its derivatives; HMG-CoA reductaseinhibitors such as mevastatin, pravastatin, and simvastatin; gemfibroziland other fibric acids, such as gemfibrozil, clofibrate, fenofibrate,benzafibrate and cipofibrate; probucol; raloxifene and its derivatives;and mixtures thereof.

The compounds and compositions also find use in a variety of in vitroand in vivo assays, including diagnostic assays. For example, variousallotypic LDL receptor gene expression processes may be distinguished insensitivity assays with the subject compounds and compositions, orpanels thereof. In certain assays and in in vivo distribution studies,it is desirable to used labeled versions of the subject compounds andcompositions, e.g. radioligand displacement assays. Accordingly, theinvention provides the subject compounds and compositions comprising adetectable label, which may be spectroscopic (e.g. flurescent),radioactive, etc.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES

¹ H NMR spectra were recorded on a Varian Gemini 400 MHz NMRspectrometer. Significant peaks are tabulated in the order: multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), couplingconstant(s) in Hertz, number of protons. Electron Ionization (EI) massspectra were recorded on a Hewlett Packard 5989A mass spectrometer FastAtom Bombardment (FAB) mass spectroscopy was carried out in a VGanalytical ZAB 2-SE high field mass spectrometer. Mass spectroscopyresults are reported as the ratio of mass over charge, and the relativeabundance of the ion is reported in parentheses.

Example 1 ##STR9##4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene. ToN,N-dimethyl-1,4-phenyldiamine dihydrochloride (3 g, 14.6 mmol)suspended in pyridine (50 mL) at 0° C. under argon was added dropwisepentafluorophenylsulfonyl chloride (2.38 mL, 16 mmol). The reactionmixture was stirred for 30 min at 0° C. and allowed to warm to ambienttemperature. The reaction mixture was stirred at room temperature for3h. The volume of the mixture was then reduced to 10 mL under reducedpressure. The mixture was diluted with ethyl acetate and the reactionquenched with water. The layers were separated and the aqueous layerextracted twice with ethyl acetate. The organic layers were combined andwashed with brine and dried with MgSO₄. The solvent was evaporated andthe residue purified by chromatography on silica, eluting with CH₂ Cl₂.The title product was obtained as a white solid in 63% yield (3.4 g). ¹H NMR (CDCl₃): 7.01(d, J=8.9 Hz, 2H), 6.77(s, 1H), 6.59(d, J=8.3 Hz,2H), 2.92 ppm (s, 6H). FAB m/z (relative abundance): 367(100%, M+H+),135(30%), 121(25%). Anal. calcd. for C₁₄ H₁₁ F₅ N₂ O₂ S: C45.95, H 3.03,N 7.65. Found C, 45.83, H 2.99, N 7.62 Example 2 ##STR10##

3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₃): 7.12(t, J=8 Hz, 1H), 7.05(s, 1H), 6.57(s, 1H) 6.53(d, J=8 Hz,1H), 6.40(d, J=8 Hz, 1H), 2.94 ppm (s, 6H). FAB m/z: 366(100%, M⁺). Thecompound was prepared by protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with3-(N,N-dimethylaiino)aniline.

Example 3 ##STR11##

1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene. ¹ H NMR (CDCl₃)6.97(s, 1H), 6.76(d, J=8.6 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 6.62(dd,J=8.6, 2.6 Hz, 1H), 4.21 ppm (s, 4H). FAB m/z: 381(100%, M+H+). Analcalcd. for C₁₄ H₈ F₅ NO₄ S: C 44.09, H, 2.12, N, 3.68, S, 8.39. Found:C, 43.83, H, 2.19, N, 3.62, S, 8.20. The compound was prepared by aprotocol similar to that of example 1 by replacingN,N,-dimethyl-1,4-phenyldiamine dihydrochloride with3,4-ethylenedioxyaniline.

Example 4 ##STR12##

1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₃): 6.85(s, 1H), 6.78(s, 1H), 6.70(d, J=8 Hz, 1H), 6.57(d, J=8 Hz,1H), 5.97 ppm (s, 2H). The compound was prepared by a protocol similarto that of example 1 by replacing N,N-dimethyl-1,4-phenyldiaminedihydrochloride with 3,4-methylenedioxyaniline.

Example 5 ##STR13##

1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene. ¹ H NMR (CDCl₃):6.98(s, 1H), 6.85(d, 1H), 6.74(d, 1H), 6.60(dd, 1H), 3.85(s, 3H), 3.83ppm (s, 3H). EI, m/z: 383(50, M⁺), 152(100). The compound was preparedby a protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with3,4-dimethoxyaniline.

Example 6 ##STR14##

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₃): 6.93(s, 1H), 6.7-6.8(m, 3H), 5.68(bs, 1H), 3.85ppm (s, 3H). EI,m/z: 333(20, M⁺), 138(100). mp 118-120° C. The compound was prepared bya protocol similar to that of example 1 by replacingN,N,-dimethyl-1,4-phenyldiamine dihydrochloride with3-hydroxy4-methoxyaniline.

Example 7 ##STR15##

2-Fluoro-1-methoxy-4-pentafluorosulfonamidobenzene. ¹ H NMR (DMSO)11.15(broad s, 1H), 7.13(t, J=9Hz, 1H), 7.02 (dd, J=9.5 2.5 Hz, 1H),6.94 ppm (dd. J=8.8 1.5 Hz, 1H), 3.79 ppm (s, 3H). EI, m/z: 371 (20,M⁺), 140 (100). Anal. calcd. for C₁₃ H₇ HF₆ N₁ O₃ S₁ : C, 42.06, H,1.90, N, 3.77, S, 8.64. Found: C, 42.19, H, 1.83, N, 3.70, S, 8.60. Mp118-119° C. The compound was prepared by a protocol similar to that ofexample 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 3-fluoro-p-anisidine.

Example 8 ##STR16##

4-Methoxy-1-pentafluorophenylsulfonamidobenzene. 1H NMR (CDCl₃): 6.99(s,1H), 6.96(d, J=4 Hz, 2H), 6.88 (d, J=4 Hz, 2H), 3.83 ppm (s, 3H). EI,m/z: 353 (60, M⁺), 122 (100). M.p. 102-103° C. The compound was preparedby a protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with 4-methoxyaniline.

Example 9 ##STR17##

3-Hydroxy-1-pentafluorophenylsulfonamidobenzene. ¹ H NMR (CD₃ OD):7.15(t, J=8.1 Hz, 1H), 6.67(t, J=2.2 Hz, 1H) 6.60(dd, J=1.3 Hz, 7.8 Hz,1H), 6.52 ppm (dd. J=2.4 Hz 8.3 Hz, 1H). EI, m/z: 339 (80, M⁺), 256(50),81 (100). The compound was prepared by a protocol similar to that ofexample 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 3-hydroxyaniline.

Example 10 ##STR18##

4-Hydroxy-1-pentafluorosulfonamidobenzene. ¹ H NMR (CD₃ OD): 6.95(d,J=8.9 Hz, 2H), 6.65 ppm (d, J=8.9 Hz, 2H). EI, m/z: 339 (30, M⁺). Thecompound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with4-hydroxyaniline.

Example 11 ##STR19##

1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene. ¹ H NMR (CDCl₃):7.03 (d, J=7.9 Hz, 1H), 6.92(s, 1H), 6.85-6.82(m, 2H), 2.18(s, 3H), 2.16ppm (s, 3H). The compound was prepared by a protocol similar to that ofexample 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 3,4-dimethylaniline.

Example 12 ##STR20##

4-(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₁₃): 6.93(d, J=8.8 Hz, 2H), 6.78(s, 1), 6.45(d, J=8.7 Hz, 2H), 3.25(dd, J=7.0 Hz, 7.3 Hz,4H), 1.10 ppm (t, J=7.2 Hz, 6H). The compound wasprepared by a protocol similar to that of example 1 by replacingNN-dimethyl-1,4-phenyldiamine dihydrochloride with4-(N,N-diethylamino)aniline.

Example 13 ##STR21##

4-Amino-1-pentafluorophenylsulfonamidobenzene. ¹ H NMR (CDCl₃): 6.82(d,J=8.7 Hz, 2H), 6.49 ppm (d, J=8.7 Hz, 2H). EI, m/z: 338(7, M⁺),107(100), 80(40). The compound was prepared by a protocol similar tothat of example 1 by replacing N,N-dimethyl-1,4-phenyldiaminedihydrochloride with 1,4-diaminobenzene.

Example 14 ##STR22##

Pentafluorophenylsulfonamidobenzene. ¹ H NMR (CDCl₃): 7.30(d, J=8 Hz,2H), 7.13-7.2(m, 3H), 7.0 ppm (s, 1H). EI, m/z: 323 (90, M⁺), 92(100).The compound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with aniline.

Example 15 ##STR23##

5-Pentafluorophenylsulfonamidoindazole. ¹ H NMR (CD₃ OD): 7.98(s, 1H),7.6(s, 1H), 7.47(d, J=8.3 Hz, 1H), 7.23 ppm (d. J=8.3 Hz, 1H). EI m/z:364(50, M+H⁺), 133(100). The compound was prepared by a protocol similarto that of example 1 by replacing N,N-dimethyl-1,4-phenyldiaminedihydrochloride with 5-aminoindazole.

Example 16 ##STR24##

5-Pentafluorophenylsulfonamidoindole. ¹ H NMR (CDCl₃): 8.2(s, 1H),7.43(s, 1H), 7.3(d, J=8 Hz, 1H), 7.22(s, 1H)), 6.98(d, J=8 Hz, 1H), 6.92ppm (s, 1H), 6.50 ppm (s, 1H). EI m/z: 362(M⁺), 131(100). The compoundwas prepared by a protocol similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with 5-aminoindole.

Example 17 ##STR25##

4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonamido)benzene.4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg,0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system wasadded under N₂ at room temperature a 1M solution of lithiumbis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirredfor 10 min followed by addition of Mel (65 mg, 0.028 mL). The reactionmixture was stirred overnight, the solvent was evaporated under reducedpressure and the crude product purified by HPLC using silica as thestationary phase and eluting with 20% EtOAc/Hex (v/v) to afford theproduct as a white solid in 60% yield (62 mg). EI m/z: 380(35, M⁺),149(100). ¹ H NMR (CD₃ OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H),3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C₁₅ H₁₃ F₅ SO₂ N₂ : C, 47.37,H, 3.45, N 7.37. Found: C, 47.37, H, 3.49, N, 7.32.

Example 18 ##STR26##

1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene. 1-Hydroxy-²-methoxy-4-pentafluorophenylsulfonamidobenzene (250 mg, 0.678 mmol) wassuspended in dry CH₂ Cl₂ (5 mL) at 0° C. under nitrogen. To the mixturewas added BBr₃ as a 1M solution in CH₂ Cl₂ (0.746 mmol, 1.1 eq.). Themixture was warmed to ambient temperature and stirred overnight. Thereaction mixture was poured over ice (75 mL) and extracted 3 times with30 mL portions of CH₂ Cl₂. The organic layer was dried with MgSO₄, andthe solvent was evaporated. The crude product was purified bychromatography over silica eluting with 30% (v/v) EtOAc/Hex to affordthe product as a white solid in 41% yield (98 mg). ¹ H NMR (DMSO):10.63(s, 1H), 9.15(s, 1H), 8.91(s, 1H), 6.61(d, J=9 Hz, 1H), 6.58(d, J=3Hz, 1H), 6.39 ppm(dd, J=9 Hz 3 Hz, 1H).

Example 19 ##STR27##

4-Ethoxy-1-pentafluorophenylsulfonamidobenzene. To a stirred solution ofp-phenetidine (0.100 g, 0.729 mmol) in dimethylformamide (3.65 mL) at25° C. was added pentafluorophenyl sulfonyl chloride (0.135 mL, 0.911mmol), followed by sodium carbonate (0.116 g, 1.09 mmol), and thereaction mixture was stirred for 18 hours. The reaction mixture wasdiluted with ethyl acetate (50 mL) and washed with 20% ammonium chloride(2×20 mL) and saturated sodium chloride (2×20 mL). The organic layer wasdried (sodium sulfite), and the ethyl acetate was removed under reducedpressure to yield a reddish-brown oil. Column chromatography (3:1 ethylacetate/hexane) yielded the title compound (0.222 g, 83%). ¹ H NMR(CDCl₃) 7.08(d, J=9 Hz, 2H), 7.04(s, 1H), 6.80 (d, J=9 Hz, 2H), 3.96(q,J=7 Hz, 2H), 1.37 ppm (t, J=7 Hz, 2H). IR (neat) 3000-3600, 1750 cm⁻¹.EI m/z : 367(M⁺), 154, 136.

The compounds of Examples 20 through 26 were prepared by a protocolsimilar to that of Example 19 by replacing p-phenetidine with theappropriate amine.

Example 20 ##STR28##

3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3,5-dimethoxyaniline. ¹ H NMR (CDCl₃) 6.91(s, 1H),6.32(s, 2H), 6.25(s, 1H), 3.72 ppm (s, 6H).

Example 21 ##STR29##

3-Ethoxy-1-pentafluorophenylsulfonamidobenzene . The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3-ethoxyaniline. ¹ H NMR (CDCl₃) 7.35 (t, J=8 Hz.1H), 7.21(s, 1H), 6.92(s, 1H), 6.86(d, J=8 Hz, 1H), 6.83(d, J=8 Hz, 1H),4.15(q, J=6 Hz, 2H), 1.56 ppm (t, J=6 Hz, 3H).

Example 22 ##STR30##

7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 2-amino-7-hydroxynaphthalene. ¹ H NMR (CDCl₃) 8.15(t,J=8 Hz, 1H), 7.55(d, J=8 Hz, 1H), 7.44(s, 1H), 7.42(d, J=8 Hz, 1H),7.40(s, 1H), 6.88 ppm (q, J=8 Hz, 1H).

Example 23 ##STR31##

3-Phenoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3-phenoxyaniline. ¹ H NMR (CDCl₃) 7.34(t, J=8 Hz,2H), 7.26(t, J=8 Hz, 1H), 7.16(t, J=8 Hz, 1H), 6.94(d, J=8 Hz, 2H),6.86(d, J=8 Hz, 1H), 6.82(d, J=8 Hz, 1H), 6.74(s, 1H).

Example 24 ##STR32##

3-Methoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3-methoxyaniline. ¹ H NMR (CDCl₃) 7.20(d, J=8 Hz,1H,), 6.95(s, 1H), 6.78(d, J=8 Hz, 1H,), 6.70(t, J=8 Hz, 1H), 3.79 ppm(s, 1H).

Example 25 ##STR33##

4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 4-(1-morpholino)aniline. ¹ H NMR (CDCl₃) 7.09(d, J=8Hz, 2H), 6.85(d, J=8 Hz, 2H), 3.85(t, J=8 Hz, 4H), 3.15 ppm (t, J=8 Hz,4H).

Example 26 ##STR34##

5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene. The compound wasprepared by a protocol similar to that of Example 19 by replacingp-phenetidine with 3,4,5-trimethoxyaniline. ¹ H NMR (CDCl₃) 8.14(s, 1H),6.46(s, 2H), 3.69(s, 6H), 3.59(s, 3H).

Example 27

1,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene .1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene.5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene.1,2,3-Methoxy-5-pentafluorophenylsulfonamidobenzene (269 mg, 0.65 mmol)was suspended in dry CH₂ Cl₂ (5 mL) at 0° C. under nitrogen. To themixture was added BBr₃ as 1M solution in CH₂ Cl₂ (3.26 mmol, 5eq.). Themixture was warmed to ambient temperature and stirred overnight. Thereaction mixture was poured over ice (75 mL) and extracted 3 times with30 mL portions of CH₂ Cl₂. The organic layer was dried with MgSO₄,evaporated, and the residue was subjected to chromatography over silicaeluting with 30% (v/v) EtOAc/Hex to afford the three products. Thecompounds of Examples 28 and 29 were prepared in a manner similar tothat described above beginning with the product of Example 20 andtreating it with BBr₃. ##STR35##

1,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₃) 10.85(s, 1H), 8.31(s, 1H), 6.41(s, 2H), 3.66 ppm (s, 6H).##STR36##

1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₃) 10.73(s, 1H), 8.31(s, 1H), 6.27(s, 1H), 6.26(s, 1H), 3.66 ppm(s, 3H). ##STR37##

5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene. ¹ H NMR (CDCl₃)11.0(s, 1H), 9.03(s, 2H), 8.06(s, 1H), 6.13 ppm (s, 2H).

Example 28 ##STR38##

3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₃) 11.2(s, 1H), 9.63(s, 1H), 6.23(s, 1H), 6.21(s, 1H), 6.08(s, 1H),3.63(s, 3H).

Example 29 ##STR39##

3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene. ¹ H NMR (CDCl₃)7.15(s, 1H), 6.25(s, 2H), 6.15(s, 1H), 5.31(s, 2H).

Example 30 ##STR40##

2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene.Prepared using a procedure similar to that of Example 18 replacing4(N,N-dimethylamino)-1-pentafluorophenylsulfonamidobenzene with theappropriate non-substituted sulfonamide (product of Example 7). ¹ H NMR(CDCl₃): 6.97-6.94(m, 2H), 6.89(t, J=9 Hz, 1H), 3.87(s, 3H), 3.35 ppm(t, J=1 Hz). EI m/z: 385(20, M⁺), 154(100). Anal calcd. for C₁₄ H₉ F₆NO₃ : C, 43.64, H, 2.35, N, 3.64. Found C, 43.55, H, 2.38, N, 3.65.

Example 31 ##STR41##

2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene. 1H NMR (CDCl₃):7.35(d, J=3 Hz, 1H), 7.15(dd, J=9 Hz, 3 Hz, 1H), 6.97(s, 1H), 6.81(d,J=9 Hz, 1H), 3.88 ppm (s, 3H). EI m/z: 433(35, M⁺), 202(100). Thecompound was prepared by a protocol similar to that of example 1 byreplacing N,N-dimethyl-1,4-phenyldiamine dihydrochloride with3-bromo4-methoxyaniline.

Example 32 ##STR42##

2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene. ¹ H NMR(CDCl₃): 7.19(d, J=3 Hz, 1H), 7.08(dd, J=9 Hz, 3 Hz, 1H), 7.01(s, 1H),6.84(d, J=9 Hz, 1H), 3.85 ppm (s, 3H). EI m/z(rel. abundance): 387(10,M⁺), 156(100). The compound was prepared by a protocol similar to thatof example 1 by replacing N,N-dimethyl-1,4-phenyldiamine dihydrochloridewith 3-chloro4-methoxyaniline.

Example 33 ##STR43##

4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzenehydrochloride.4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene (2 g, 5.5mmol) was dissolved in 15 mL of diethyl ether at ambient temperatureunder nitrogen. Gaseous HCl was bubbled into the reaction mixture for 5min. The mixture was filtered and the resulting solid washed twice with15 mL portions of ice cold diethyl ether to afford the product as awhite solid (1.89 g, 86% yield). ¹ H NMR (CD₃ OD): 7.62(dd, J=9.0 Hz,1.6 Hz, 2H), 7.44(dd, J=9.0 Hz, 1.6 Hz, 2H), 3.28 ppm (s, 6H). FAB m/z:367(100%, M+H⁺), 135(90%), 121(45%). Anal. calcd. for C₁₄ H₁₃ ClF₅ N₂ O₂S: C, 41.79, H, 3.01, N, 6.97, S, 7.95. Found C, 41.71, H, 3.05, N,7.01,S, 7.96.

Example 34 ##STR44##

3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with 3,4-difluoroaniline.¹ H NMR (CDCl₃) 7.13(m, 3H), 6.91 ppm (m, 1H). EI, m/z (relativeabundance): 359(20), 128(100). Anal. calcd for C13H4F7N1O2S1: C, 40.12,H, 1.12, N, 3.90. Found: C, 40.23, H, 1.17, N, 3.89.

Example 35 ##STR45##

4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene. The compoundwas prepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with4-(trifluoromethoxy)aniline. ¹ H NMR (CDCl₃) 7.18 ppm (m, 4H). EI, m/z(relative abundance): 407(20), 176(100). Anal. calcd. for C13H5F8N1O3S1:C, 38.34, H, 1.24, N, 3.44. Found: C, 38.33, H, 1.30, N, 3.43.

Example 36 ##STR46##

2-Chloro-5-pentafluorophenylsulfonamidopyridine. The compound wasprepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride with5-amino-2-chloropyridine. H NMR (DMSO-d⁶): 8.18(d, J=2.68 Hz. 1H),7.64(dd, J=8.75, 2.89 Hz, 1H), 7.50 ppm (d, J=8.75 Hz, 1H). EI m/z358(20, M⁺), 127(100). Anal. calcd. for C₁₁ H₄ ClF₅ N₂ O₂ S: C, 36.83,H, 1.12, N, 7.81, S, 8.94, Cl, 9.90. Found: C, 37.00, H, 1.16, N, 7.78,S, 8.98, Cl, 10.01. White crystals with M.P.=144-145° C.

Example 37 ##STR47##

2-Hydroxy-1-methoxy-4-(N-(5-hydroxypentyl)-pentafluorophenylsulfonamido)benzene.N-(5-hydroxypentyl)-2-hydroxy-1-methoxy-4-aminobenzene was prepared byreductive amination of 5-amino-2-methoxy phenol with glutaric dialdehydewith NaBH₄ in MeOH.2-Hydroxy-1-methoxy-4-(N-(5-hydroxypentyl)-pentafluorophenylsulfonamido)benzenewas prepared in a manner similar to that of example 1 by replacingN,N-dimethyl-1,4-phenyldiamine dihydrochloride withN-(5-hydroxypentyl)-2-hydroxy-1-methoxy-4-aminobenzene. ¹ H NMR (CDCl₃):6.78(d, J=8.6 Hz, 1H), 6.71(dd, J=8.59, 2.48 Hz, 1H), 6.63(d, J=2.48 Hz,1H), 3.88(s, 3H), 3.7(t, J=6.8 Hz, 2H), 3.6(t, J=6.39 Hz, 2H), 1.5 ppm(m, 6H). Anal. calcd. for C₁₈ H₁₈ F₅ NO₅ S: C, 47.47, H, 3.98, N, 3.08,S, 7.04. Found: C, 47.47, H, 4.04, N, 3.11, S, 6.97. White crystals withM.P.=118°.

Example 38 ##STR48##

4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene. Thecompound was prepared in a manner similar to example 46 by replacing3-chloroaniline with 4-t-butoxyaniline. 4-t-Butoxyaniline was preparedby the method of Day (J Med Chem. 1975, 18, 1065). ¹ H NMR (CDCl₃): d,7.07(m, 2), 6.92(m, 2), 6.88(m, 1), 1.31(s, 9). MS (EI): m/z 395(1, M⁺),339(28), 108(100). Anal. Calcd. for C₁₆ H₁₄ F₅ NO₃ S: C, 48.61; H, 3.57;N, 3.54; S, 8.11. Found: C, 48.53; H, 3.60; N, 3.50; S, 8.02.

Example 39 ##STR49##

1-Bromo-3-hydroxy4-methoxy-1-pentafluorophenylsulfonamidobenzene. Thecompound was prepared by bromination of the compound of example 6 withN-bromosuccinimide in dichloromethane. ¹ H NMR (CDCl₃) 7.28(br s, 1H),7.21(d, J=9 Hz, 1H), 6.80(d, J=9 Hz, 1H), 6.05(s, 1H), 3.89 ppm (s, 3H).EI, m/z (relative abundance): 449(25), 447(25), 218 (100), 216(100).Anal. calcd. for C13H8Br1F5N1O4S1: C, 34.84, H, 1.57, N :3.13, S, 7.15.Found: C, 34.75, H, 1.60, N, 3.07, S, 7.08.

Example 40 ##STR50##

2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene. Thecompound was prepared by bromination of the compound of example 6 withN-bromosuccinimide in dichloromethane. ¹ H NMR (CDCl₃) 7.28(s, 1H),7.16(br s, 1H), 6.91(s, 1H), 5.63(s, 1H), 3.85 ppm (s, 3H). EI, m/z(relative abundance): 449(25), 447(25), 218(100), 216(100). Anal. calcd.for C13H8Br1F5N1O4S1: C, 34.84, H, 1.57, N, 3.13, S, 7.15. Found: C,34.84, H, 1.57, N, 3.05, S, 7.06.

Example 41 ##STR51##

1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene. Thecompound was prepared by bromination of the compound of example 7 withbromine water. ¹ H NMR (CDCl₃): 7.49(d, J=11.72 Hz, 1H), 7.21(s, 1H),7.04(d, J=8.2 Hz, 1H), 3.84 ppm (s, 3H). EI m/z: 449(20, M⁺), 451(20),228(100), 230(100). Anal. Calcd. for C₁₃ H₆ BrF₆ NO₃ S: C, 34.69, H,1.34, N, 3.11, S, 7.12, Br, 17.75. Found: C, 34.76, H, 1.29, N, 3.05, S,7.12, Br 17.68. White crystals with M.P.=109° C.

Example 42 ##STR52##

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene sodium salt.The compound was prepared by treating the compound of example 6 with anequimolar amount of 1N NaOH.sub.(aq). The mixture was then lyophilizedand the residue recrystallyzed from ethyl acetate ether. ¹ H NMR (DMSO)8.40(s, 1H), 6.57(d, J=9 Hz, 1H), 6.39(d, J=2 Hz, 1H), 6.24(dd, J=9, 2Hz, 1H), 3.62 ppm (s, 3H). Anal. calcd. for C13H7F5N1Na1O4S1: C, 39.91,H, 1.80, N, 3.58, Na, 5.88, S, 8.19. Found: C, 39.79, H, 1.86, N, 3.50,Na 5.78, S, 8.07.

Example 43 ##STR53##

2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene potassiumsalt. The compound was prepared in a manner similar to that of example42 by replacing 1N NaOH with 1N KOH. ¹ H NMR (DMSO) 8.30(br, s, 1H),6.55(d, J=9 Hz, 1H), 6.36(d, J=2 Hz, 1H), 6.25(dd, J=9, 2 Hz, 1H), 3.61ppm (s, 3H). Anal. calcd. for C13H7F5K1N1O4S1: C, 38.33, H, 1.73, N,3.44, S, 7.87. Found: C, 38.09, H, 1.79, N, 3.39, S, 7.97.

Example 44 ##STR54##

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene potassium salt.The compound was prepared in a manner similar to that of example 43 byreplacing the compound from example 6 with example 7. ¹ H NMR (DMSO)6.80(t, J=10 Hz, 1H), 6.72(dd, J=9, 2 Hz, 1H), 6.54(dd, J=9, 2 Hz, 1H),3.68 ppm (s, 3H). Anal. calcd. for C13H6F6K1N1O3S1: C, 38.15, H, 1.48,N, 3.42, S, 7.83. Found: C, 38.09, H, 1.51, N, 3.35, S, 7.73.M.P.=202-205° C.

Example 45 ##STR55##

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene sodium salt.The compound was prepared in a manner similar to that of example 44 byreplacing iN KOH with 1N NaOH. ¹ H NMR (DMSO) 6.80(t, J=10 Hz, 1H),6.71(dd, J=9, 2 Hz, 1H), 6.53(dd, J=9, 2 Hz, 1H), 3.69 ppm (s, 3H).Anal. calcd. for C13H6F6N1Na1O3S1: C, 39.71, H, 1.54, N, 3.56, Na 5.85,S, 8.15. Found: C, 39.56, H, 1.62, N, 3.49, Na, 5.88, S, 8.08. M.P.>250°C.

Example 46 ##STR56##

3-Chloro-1-pentafluorophenylsulfonamidobenzene. To a solution ofpentafluorophenylsulfonyl chloride (0.15 mL, 1.00 mmol) in MeOH (4 mL)was added 3-chloroaniline (260 mg, 2.04 mmol). After stirring at rt for1 h, the reaction mixture was concentrated under reduced pressure andthe residue was taken up in EtOAc and then filtered through a plug ofsilica gel. The filtrate was concentrated to give a yellow oil that uponchromatography provided, 265 mg (74%) of product. ¹ H NMR (CDCl₃): d,7.28-7.24(m, 1H), 7.21-7.17(m, 2H), 7.10-7.08(m, 1H), 7.07(s, 1H). MS(EI): m/z 357(42, M⁺), 258 (76), 126(87), 99(100). Anal. Calcd. for C₁₂H₅ ClF₅ NO₂ S: C, 40.30; H, 1.41; N, 3.92; S, 8.96. Found: C, 40.18; H,1.35; N, 3.84; S, 8.90.

Example 47 ##STR57##

4-Chloro-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 46 byreplacing 3-chloroaniline with. 4-chloroaniline. ¹ H NMR (CDCl₃): d,7.30(m, 2H), 7.20(m, 1H), 7.14(m, 2H), MS (EI): m/z 357(27, M⁺),258(38), 126(100), 99(85). Anal. Calcd. for C₁₂ H₅ ClF₅ NO₂ S: C, 40.30;H, 1.41; N, 3.92; S, 8.96. Found: C, 40.19; H, 1.37; N, 3.87; S, 8.88.

Example 48 ##STR58##

3-Nitro-1-pentafluorophenylsulfonamidobenzene. The compound was preparedin a manner similar to that described in example 46 by replacing3-chloroaniline with 3-nitroaniline. ¹ H NMR (CDCl₃): d, 8.14(s, 1H),8.06-8.03(m, 2H), 7.66-7.63(m, 1H), 7.55(m, 1H) MS (EI): m/z 368(54,M⁺), 137(70), 91(100). Anal. Calcd. for C₁₂ H₅ F₅ N₂ O₄ S: C, 39.14; H,1.37; N, 7.61; S, 8.71. Found: C, 39.39; H, 1.45; N, 7.46; S, 8.58.

Example 49 ##STR59##

4-Methoxy-1-pentafluorophenylsulfonamido-3-trifluoromethylbenzene. Thecompound was prepared in a manner similar to that described in example46 by replacing 3-chloroaniline with 4-methoxy-3-trifluoromethylanilinewhich was obtained by the hydrogenation of the corresponding nitrocompound. White solid, mp 121-123° C. ¹ H NMR (CDCl₃): d, 7.43-7.37(m.2H), 6.96(d, J=8.8, 1H), 3.88(s, 3H). MS (EI): m/z 421(16, M⁺),190(100). Anal. Calcd. for C₁₄ H₇ F₈ NO₃ S: C, 39.92; H, 1.67; N, 3.32;S, 7.61. Found: C, 40.17; H, 1.68; N, 3.28; S, 7.67.

Example 50 ##STR60##

4-Methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene. To asolution of 4-methoxy-1-pentafluorophenylsulfonamidobenzene (448 mg,1.27 mmol) in THF (3 mL) was added triphenylphosphine (333 mg, 1.27mmol) and allyl alcohol (0.09 mL, 1.27 mmol). Diethylazodicarboxylate(0.20 mL, 1.27 mmol) was added and the mixture was stirred at rt. After1 h, the reaction mixture was poured onto saturated NaCl (10 mL) andextracted with CH₂ Cl₂ (3×10 mL). The combined organic extracts werewashed with saturated NaHCO₃ (10 mL) and dried (MgSO₄). Concentrationfollowed by flash chromatography (25:25:1/hexanes:CH₂ Cl₂ :EtOAc)provided 451 mg (90%) of product as a white solid, mp 59-60° C. 1H NMR(CDCl₃): d, 7.06(m, 2H), 6.85(m, 2H), 5.79(m, 1H), 5.15(s, 1H), 5.11 (m,1H), 4.37(d, J=6.3, 2H), 3.80(s, 3H). MS (EI): m/z 393(33, M⁺),162(100), 134(66). Anal. Calcd. for C₁₆ H₁₁ F₅ NO₃ S: C, 48.98; H, 2.83;N, 3.57; S, 8.17. Found: C, 49.13; H, 3.15; N, 3.63; S, 8.15.

Example 51 ##STR61##

1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene. Thecompound was prepared in a manner similar to that described in example50 by replacing allyl alcohol with 3-buten-1-ol. White solid, mp 64-66°C. 1H NMR (CDCl₃): d, 7.08(m, 2H), 6.86(m, 2H), 5.74(m, 1H),5.10-5.04(m, 2H), 3.83(m, 2H), 3.81(s, 3H), 2.25(q, J=6.9, 2H). MS (EI):m/z 407(13, M⁺), 366(24), 135(100). Anal. Calcd. for C₁₇ H₁₄ F₅ NO₃ S:C, 50.13; H, 3.46; N, 3.44; S, 7.87. Found: C, 50.25: H, 3.51; N, 3.43;S, 7.81.

Example 52 ##STR62##

4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. Thecompound was prepared in a manner similar to that described in example50 by replacing allyl alcohol with 4-penten-1-ol. Low meltingsemi-solid. ¹ H NMR (CDCl₃): d, 7.08(m, 2H), 6.87(m, 2H), 5.74(m, 1H),5.02-4.96(m, 2H), 3.81(s, 3H), 3.76(t, J=7.04, 2H), 2.11(q, J=6.9, 2H),1.60(pentet, J=7.3, 2H). MS (EI): m/z 421(30, M⁺), 190(100). Anal.Calcd. for C₁₈ H₁₆ F₅ NO₃ S: C, 51.31; H, 3.83; N, 3.32; S, 7.61. Found:C, 51.44; H, 3.89; N, 3.38; S, 7.54.

Example 53 ##STR63##

1-(N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido)4-methoxybenzene.To a solution of4-methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene (101 mg,0.26 mmol) in acetone:water (8:1, 1 mL) at rt was addedN-methylmorpholine N-oxide (34.0 mg, 0.29 mmol) and OsO₄ (0.10 mL of0.16M solution in H₂ O, 1.60×10⁻² mmol). After stirring at rt for 18 h,the reaction mixture was treated with saturated NaHSO₃ (5 mL) andallowed to stir at rt. After 1 h, the reaction mixture was poured ontosaturated NaHSO₃ (5 mL) and extracted with CH₂ Cl₂ (3×10 mL). Thecombined organic extracts were dried (MgSO4) and concentrated. Flashchromatography (1:1, 1:2/hexanes:EtOAc) afforded 90 mg (83%) of productas a white solid, mp 130-131° C. ¹ H NMR (CDCl₃): d, 7.11(m, 2H), 6.85(m, 2H), 3.78(s, 3H), 3.90-3.65(m, 5H). Anal. Calcd. for C₁₆ H₁₃ F₅ NO₅S: C, 45.08; H, 3.07; N, 3.29; S, 7.52. Found: C, 45.09; H, 3.33; N,3.27; S, 7.46.

Example 54 ##STR64##

1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene.The compound was prepared in a manner similar to that described inexample 53 by replacing4-methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene with1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene. Whitesolid, mp 126-128° C. ¹ H NMR (CDCl₃): d, 7.10(m, 2H), 6.88(m, 2H),4.13(m, 1H), 3.96(m, 1H), 3.81(s, 3H), 3.78-3.73(m, 1H), 3.64(dd, 1,J=2.9, 10.7, 1H), 3.47(dd, J=7.3, 11.2; 1H), 2.67(bs, 1H), 1.92(bs, 1H),1.62(m, 2H).

Example 55 ##STR65##

1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene.The compound was prepared in a manner similar to that described inexample 53 by replacing4-methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene with4-methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. Whitesolid, mp 116-118° C. ¹ H NMR (CDCl₃): d, 7.07(m, 2H), 6.86(m, 2H),3.80(s, 3H), 3.78(m, 2H), 3.71-3.62(m, 2H), 3.43(dd, J=7.5, 10.8; 1H),1.90(bs, 2H), 1.66-1.49(m, 4H). Anal. Calcd. for C₁₈ H₁₈ F₅ NO₅ S: C,47.48; H, 3.98; N, 3.08; S, 7.04. Found: C, 47.58; H,3.95; N, 3.06; S,6.95.

Example 56 ##STR66##

1)pentafluorophenylsulfonamido)4-methoxybenzene. To a solution of1-(N-(3-butenyl)pentafluorophenylsulfonamido)4-methoxybenzene (410 mg,1.01 mmol) in THF (6.5 mL) at -78° C. was added BH₃.THF (1.00 mL of a 1Msolution in THF, 1.00 mmol). After stirring at -78° C. for 1 h and at 0°C. for 1 h, the reaction mixture was treated with H₂ O (20 mL) andsodium perborate (513 mg, 5.14 mmol). After stirring at rt for 2 h, themixture was poured onto H₂ O (20 mL) and extracted with CH₂ Cl₂ (3×15mL). The combined organic extracts were washed with sat. NaCl (20 mL)and dried (MgSO₄). Concentration followed by chromatography(2:1/hexanes:EtOAc) afforded 270 rag (64%) of product as a white solid,mp 88-90° C. ¹ H NMR (CDCl₃): d, 7.08(m, 2H), 6.85(m, 2H), 3.80(s, 3H),3.77(m, 2H), 3.64(t, J=6.0; 2H), 1.63-1.55(m, 5H), 1.50(bs, 1H). Anal.Calcd. for C₁₇ H₁₆ F₅ NO₄ S: C, 48.00; H, 3.79; N, 3.29; S, 7.54. Found:C, 48.08; H, 3.76; N, 3.34; S, 7.46.

Example 57 ##STR67##

4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)benzene.The compound was prepared in a manner similar to that described inexample 56 by replacing1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene with4-methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. Whitesolid, mp 96-97° C. ¹ H NMR (CDCl₃): d, 7.08(m, 2H), 6.86(m, 2H),3.81(s, 3H), 3.76(t, J=6.8, 2H), 3.62(t, J=6.4; 2H), 1.58-1.43(m, 6H).Anal. Calcd. for C₁₈ H₁₈ F₅ NO₄ S: C, 49.20; H, 4.13; N, 3.19; S, 7.30.Found: C, 49.11; H, 4.09; N, 3.14; S, 7.19.

Example 58 ##STR68##

4-Methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene. The compoundwas prepared in a manner similar to example 46 by replacing3-chloroaniline with 4-methoxy-3-nitroaniline which was prepared by themethod of Norris (Aust. J. Chem. 1971, 24, 1449). Orange-yellow solid,mp 95-97° C. ¹ H NMR (CDCl₃): d, 7.64(d, J=2.7; 1H), 7.51(dd, J=2.7,9.0; 1H), 7.09(s, 1H), 7.09(d, J=9.0; 1H), 3.95(s, 3H). Anal. Calcd. ForC₁₃ H₇ F₅ N₂ O₅ S: C, 39.21; H, 1.77; N, 7.03; S, 8.05. Found: C, 39.19;H, 1.73; N, 6.97; S, 7.95.

Example 59 ##STR69##

3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene. To a solutionof 4-methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene (627 mg, 1.58mmol) in ethanol (10 mL) was added, 10% Pd/C (51 mg). The resultingmixture was stirred under an atmosphere of hydrogen gas at 1 atmpressure. After 14 h, the mixture was passed through a pad of celite andthe filtrate was concentrated to give a solid residue. Silica gelchromatography (2:1, 1:1/hexanes:EtOAc) yielded, 542 mg (93%) of productas a white solid, mp 142-143° C. ¹ H NMR (DMSO-d₆) 10.64(s, 1), 6.68(d,J=8.4; 1H), 6.44(d, J=2.1; 1H), 6.30(d, J=2.1, 8.4; 1H), 4.88(bs, 2H),3.69(s, 3H). Anal. Calcd. for C₁₃ H₉ F₅ N₂ O₃ S: C, 42.40; H, 2.46; N,7.61; S, 8.71. Found: C, 42.29; H, 2.36; N, 7.52; S, 8.60.

Example 60 ##STR70##

4-Butoxy-1-pentafluorophenylsulfonamidobenzene. To a solution ofpentafluorophenylsulfonyl chloride (203 mg, 0.763 mmol) in MeOH (4 mL)was added 4-butoxyaniline (0.26 mL, 1.53 mmol). After stirring at rt for1 h, the reaction mixture was poured onto 1 M HCl (15 mL) and extractedwith CH₂ Cl₂ (3×10 mL). The combined organic extracts were washed withsaturated NaCl (10 mL) and dried (MgSO₄). Concentration followed byflash chromatography (25:25:1/hexanes: CH₂ Cl₂ :EtOAc) provided, 189 mg(63%) of product. ¹ H NMR (CDCl₃): d, 7.07(m, 2H), 6.86(s, 1H), 6.80(m,2H), 3.89(t, J=6.5; 2H), 1.73(m, 2H), 1.46(m, 2H), 0.95(t, J=7.5; 2H).MS (EI): m/z 395(30, M⁺), 164(35), 108(100). Anal. Calcd. for C₁₆ H₁₄ F₅NO₃ S: C, 48.61; H, 3.57; N, 3.54; S, 8.11. Found: C, 48.54; H, 3.53; N,3.50; S, 8.02.

Example 61 ##STR71##

1-Pentafluorophenylsulfonamido-4-phenoxybenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-phenoxyaniline. ¹ H NMR (CDCl₃):7.36-7.30(m, 2H), 7.15-7.10(m, 3H), 6.99(s, 1H), 6.98-6.90(m, 4H). MS(EI): m/z 415(32, M⁺), 184(100), 77(66). Anal. Calcd. for C₁₈ H₁₀ F₅ NO₃S: C, 52.05; H, 2.43; N, 3.27; S, 7.72. Found: C, 51.78; H, 2.45; N,3.25; S, 7.53.

Example 62 ##STR72##

4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-benzyloxyaniline. 4-Benzyloxyanilinewas obtained from the commercially available hydrochloride salt bytreatment with aqueous NaOH. ¹ H NMR (CDCl₃): 7.38-7.37(m, 4H),7.36-7.32(m, 1H), 7.10-7.08(m, 2H), 7.91-7.88(m, 2H), 6.78(s, 1H),5.01(s, 1H). MS (EI): m/z 429(19, M⁺), 91(100). Anal. Calcd. for C₁₉ H₁₂F₅ NO₃ S: C, 53.14; H, 2.82; N, 3.26; S, 7.45. Found: C, 53.07; H, 2.78;N, 3.21; S, 7.35.

Example 63 ##STR73##

4-Methylmercapto-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-(methylmercapto)aniline. ¹ H NMR(CDCl₃): 7.17(m, 2H), 7.09(m, 2H), 6.89(m, 1H), 2.44(s, 3H). MS (EI):m/z 369(24, M⁺), 138(100), 77(66). Anal. Calcd. for C₁₃ H₈ F₅ NO₂ S₂ :C, 42.28; H, 2.18; N, 3.79; S, 17.36. Found: C, 42.20; H, 2.21; N, 3.72;S, 17.28.

Example 64 ##STR74##

2-Methoxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with o-anisidine. ¹ H NMR (CDCl₃): d, 7.54(dd,J=1.5, 8.0; 1H), 7.13(dt, J=1.5, 8.0; 1H), 6.94(dt, J=1.2, 8.0; 1H),6.84(dd, J=1.2, 8.0; 1H), 3.79(s, 3H). MS (EI): m/z 353(82, M⁺),122(100), 94 (95). Anal. Calcd. for C₁₃ H₈ F₅ NO3S: C, 44.19; H, 2.28;N, 3.97; S, 9.06. Found: C, 44.10; H, 2.26; N, 3.92; S, 9.03.

Example 65 ##STR75##

4-Allyloxy-1-pentafluorophenylsulfonamidobenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-allyloxyaniline. 4-Allyloxyaniline wasprepared by the method of Butera (J Med. Chem. 1991, 34, 3212). ¹ H NMR(CDCl₃): 7.08(m, 2H), 6.87(m, 1H), 6.82(m, 2H), 6.04-5.94(m, 1H),5.39-5.34(m, 1H), 5.29-5.25(m, 1H), 4.48-4.46(m, 2H). MS (EI): m/z379(11, M⁺), 148(32), 41(100). Anal. Calcd. for C₁₅ H₁₀ F₅ NO₃ S: C,47.50; H, 2.66; N, 3.96; S, 8.45. Found: C, 47.53; H, 2.68; N, 3.62; S,8.37.

Example 66 ##STR76##

1-Pentafluorophenylsulfonamido-4-propoxybenzene. The compound wasprepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline with 4-propoxyaniline. 4-Propoxyaniline wasobtained by catalytic hydrogenation of 4-allyloxynitrobenzene.4-Allyloxynitrobenzene was prepared by the method of Butera (J. Med.Chem. 1991, 34, 3212). ¹ H NMR (CDCl₃): 7.09(m, 2H), 6.82(m, 2H),6.78(m, 1H), 3.87(t, J=6.5; 2H), 1.78(m, 2H), 1.02(t, J=7.4; 3H). MS(EI): m/z 381(20, M⁺), 150 (40), 108(100). Anal. Calcd. for C₁₅ H₁₂ F₅NO₃ S: C, 47.25; H, 3.17; N, 3.67; S, 8.41. Found: C, 47.01; H, 3.20; N,3.61; S, 8.31.

Example 67 ##STR77##

4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene. The compoundwas prepared in a manner similar to that described in example 60 byreplacing 4-butoxyaniline With 4-isopropoxyaniline. 4-Isopropoxyanilinewas prepared from 4-fluoronitrobenzene in analogy to the method of Day(J Med. Chem. 1975, 18, 1065). ¹ H NMR (CDCl₃): 7.08(m, 2H), 7.00(s, 1¹H), 6.81(m, 2H), 4.48(heptet, J=6.1; 1H), 1.30(d, J=6.04; 6H). MS (EI):m/z 381(7, M⁺), 339(8), 108(100). Anal. Calcd. for C₁₅ H₁₂ F₅ NO₃ S: C,47.25; H, 3.17; N, 3.67; S, 8.41. Found: C, 47.08; H, 3.18; N, 3.60; S,8.34.

Example 68 ##STR78##

1-Pentafluorophenylsulfonyloxybenzene. To a stirred solution of phenol(0.068 g, 0.729 mmol) in dimethylformamide (3.65 mL) at 25° C. is addedpentafluorophenyl sulfonyl chloride (0.135 mL, 0.911 mmol), followed bysodium carbonate (0.116 g, 1.09 mmol), and the reaction mixture isstirred for 18 hours. The reaction mixture is diluted with ethyl acetate(50 mL), washed with 20% ammonium chloride (2×20 mL), and saturatedsodium chloride (2×20 mL). The organic layer is dried (sodium sulfite),and the ethyl acetate removed under vacuum. Column chromatography (3/1ethyl acetate/hexane) yields the title compound.

Example 69 ##STR79##

1-Pentafluorophenylsulfonylindole. To a stirred solution of indole(0.085 g, 0.729 mmol) in dimethylformamide (3.65 mL) at 25° C. is addedpentafluorophenyl sulfonyl chloride (0.135 mL, 0.911 mmol), followed bysodium carbonate (0.116 g, 1.09 mmol), and the reaction mixture isstirred for 18 hours. The reaction mixture is diluted with ethyl acetate(50 mL), washed with 20% ammonium chloride (2×20 mL), and saturatedsodium chloride (2×20 mL). The organic layer is dried (sodium sulfite),and the ethyl acetate removed under vacuum. Column chromatography (3/1ethyl acetate/hexane) yields the title compound.

Example 70 ##STR80##

2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene. To3-fluoro-p-anisidine (3 g, 21.2 mmol) suspended in THF (50 mL) withpyridine (1.84 g, 23.3 mmol) at 0° C. under argon is added dropwisepentafluorophenylsulfinyl chloride (5.3 g, 21.2 mmol). The reactionmixture is stirred for 30 min. at 0° C. and allowed to warm to ambienttemperature. The reaction mixture is strirred at room temperature andfollowed by TLC. After the reaction is completed the mixture is dilutedwith ethyl acetate and the reaction quenched with water. The layers areseparated and the aqueous layer extracted twice with ethyl acetate. Theorganic layers are combined and dried with brine and with Na₂ SO₄. Thesolvent is evaporated and the residue purified by chromatography onsilica to give the title compound.

Example 71

2-Anilino-3-pentafluorophenylsulfonamidopyridine. To a solution ofpentafluorophenylsulfonyl chloride (863 mg, 3.24 mmol) in pyridine (9mL) at rt was added 3-amino-2-analinopyridine (600 mg, 3.24 mmol). Afterstirring at rt overnight the reaction mixture was concentrated atreduced pressure and the residue partitioned between 1 M Hcl (50 mL) andCH2Cl2(50 mL). The organic extract was dried and concentrated to give anoil which was purified by MPLC to give 377 mg (28%) of product as anorange solid. H¹ NMR (CDCl₃): 8.50(bs, 1H), 7.80(d, J=5.1, 1H), 7.61(d,J=8.0, 1H), 7.32(t, J=8.0, 2H), 7.25(d, J=8.0, 2H), 7.11(t, J=7.3, 1H),6.80(dd, J=5.6, 7.7, 1H), 4.20(bs, 1H). MS (FAB): m/z 438 (M^(+Na)),416(M+H).

Example 72

Compounds were evaluated for their ability to increase LDL receptorexpression in Hep G2 cells using western-blot analysis as described inTarn et al., J. Biol. Chem., 266, 16764(1991). The data presented(EC_(max)) reflect the minimum concentration at which a maximalinduction of LDL receptor was observed for each compound. In all cases,the level of induction was greater than that observed under lipid-freeconditions (activated system).

    ______________________________________                                               Compound                                                                              EC.sub.max  (μm)                                            ______________________________________                                               Example 1                                                                             0.5                                                              Example 2 5                                                                   Example 3 5                                                                   Example 4 ≦5                                                           Example 6 0.15                                                                Example 7 0.5                                                                 Example 8 0.5                                                                 Example 9 5                                                                   Example 12 5                                                                  Example 15 15                                                                 Bxample 17 5                                                                  Example 24 15                                                                 Example 25 15                                                                 Example 30 15                                                                 Example 31 ≦5                                                          Example 32 1.5                                                              ______________________________________                                    

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

What is claimed is:
 1. A compound of the formula: ##STR81## wherein R¹is selected from the group consisting of hydrogen, lower alkyl and a--CH═CH-- group attached to the 2-position of R² phenyl group forming anoptionally substituted indole; andR² is substituted phenyl; with theproviso that when R¹ is hydrogen or lower alkyl, R² is phenylsubstituted at positions 3-and, 4-, in relation to the sulfonamidogroup, with a divalent moiety that forms a 5- or 6-membered ringtogether with carbons 3- and, 4- of the phenyl ring.
 2. A compound ofclaim 1, wherein R¹ is hydrogen or lower alkyl and said divalent moietyis selected from the group consisting of --CH═CH--NH-- and --CH═N--NH--.3. A compound of claim 1, wherein said compound is selected from thegroup consisting of 5-pentafluorophenylsulfonamidoindazole and5-pentafluorophenylsulfonamidoindole.
 4. A compound of claim 1, whereinR¹ is --CH═CH-- group attached to the 2-position of R² phenyl groupforming an optionally substituted indole.
 5. A compound of claim 1,wherein said compound is 1-(pentafluorophenylsulfonyl)indole.
 6. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of the formula: ##STR82## wherein R¹ isselected from the group consisting of hydrogen, lower alkyl and a--CH═CH-- group attached to the 2-position of R² phenyl group forming anoptionally substituted indole; andR² is substituted phenyl; with theproviso that when R¹ is hydrogen or lower alkyl, R² is phenylsubstituted at positions 3- and, 4-, in relation to the sulfonamidogroup, with a divalent moiety that forms a 5- or 6-membered ringtogether with carbons 3- and, 4- of the phenyl ring.
 7. A pharmaceuticalcomposition in accordance with claim 6, wherein R¹ is hydrogen or loweralkyl and said divalent moiety is selected from the group consisting of--CH═CH--NH-- and --CH═N--NH--.
 8. A pharmaceutical composition inaccordance with claim 6, wherein said compound is selected from thegroup consisting of 5-pentafluorophenylsulfonamidoindazole and5-pentafluorophenylsulfonamidoindole.
 9. A pharmaceutical composition inaccordance with claim 6, wherein R¹ is --CH═CH-- group attached to the2-position of R² phenyl group forming an optionally substituted indole.10. A pharmaceutical composition in accordance with claim 6, whereinsaid compound is 1-(pentafluorophenylsulfonyl)indole.